Combination therapy for skin disorders

ABSTRACT

The present invention provides a novel therapeutic combination comprising one or more anti-androgen agents and one or more antibiotic/anti-inflammatory agents or pharmaceutically acceptable salts or hydrates thereof, useful for the treatment of a dermatological disorder.

RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 14/153,756, filed on Jan. 13, 2014, which is a divisionalapplication of U.S. application Ser. No. 13/518,818, filed Jun. 22, 2012now U.S. Pat. No. 8,653,129 granted on Feb. 14, 2014, which is a U.S.national phase application filed under 35 U.S.C. §371 of InternationalApplication No. PCT/US2011/031886, which was filed Apr. 11, 2011, whichclaims the benefit of the filing dates of U.S. Provisional ApplicationNo. 61/349,240, filed May 28, 2010 and 61/369,391, filed Jul. 30, 2010.The content of these earlier filed applications is hereby incorporatedby reference in the present application in its entirety.

FIELD OF THE INVENTION

The present invention is directed to a therapy comprising a novelcombination of one or more anti-androgen agents and one or moreantibiotic/anti-inflammatory agents or pharmaceutically acceptable saltsor hydrates thereof, useful for the treatment of a dermatologicaldisorder such as acne.

BACKGROUND OF THE INVENTION

Acne is a disorder of the pilosebaceous glands located on the face,chest and back. It is an almost universal disease, occurring in allraces, predominantly among adolescents. The pathogenesis of acne ismulti-factorial involving increased sebum production by the sebaceousglands, such as caused by increased activity of sebocytes, sometimes viaperoxisome proliferator-activated receptor ligands; ductalhypercomification of the pilosebaceous unit of the dermis and epidermisand hyperkeratinization (increased activity of keratinocytes);inflammation; and the presence of the anaerobic bacteriaPropionibacterium acnes (P. acnes).

The American Academy of Dermatology has reported that 85% to 100% ofthose aged 12-24 are affected by either intermittent or persistent acne,which in a number of adolescents results in scarring attributed to acne(Bershad, The Mount Sinai Journal of Medicine, Vol. 68, p. 279-286,2001; White, Journal of American Academy of Dermatology, Vol. 39, p.S34-37, 1998). Furthermore, acne can remain problematic into the thirdto fifth decades of life, particularly in women. Tan et al., (Journal ofAmerican Academy of Dermatology, Vol. 44 (Supplement 3), p. 439-445,2001), has reported that approximately 3% of all male adults and 12% ofall female adults in the U.S. suffer from acne.

There is no cure for acne. Many medications are available for treatingacne including topical retinoids (i.e., adapalene, tazarotene,tretinoin), antimicrobial and antibacterial agents (i.e., benzoylperoxide, clindamycin, erythromycin, sodium sulfacetamide with orwithout sulfur), oral antibiotics (i.e., doxycycline, minocycline,tetracycline, azithromycin, trimethoprim-sulfamethoxazole (TMP/SMX),that primarily reduces the population of P. acnes, hormonal agents asanti-androgens (i.e., oral contraceptives) that decrease sebumsecretion, systemic retinoids (i.e., isotretinoin), and topicalaminolevulinic acid plus blue light (also known as photodynamic theory).

Various agents administered in acne treatments exhibit direct orindirect antibiotic activity but also directly suppress inflammation bydecreasing neutrophil chemotaxis and down-regulate the expression ofpro-inflammatory mediators. Oral antibiotics are indicated for severalgroups of patients with inflammatory acne. They include tetracyclines(i.e., tetracycline, doxycycline, minocycline, erythromycin,clindamycin, and cotrimoxazole).

With the high incidence of acne and other dermatological disorders thatare of a major clinical health concern to both males and females, newinnovative approaches are urgently needed at both the basic science andclinical levels to decrease the incidence of dermatological disorders.

SUMMARY OF THE INVENTION

The present invention provides a novel pharmaceutical compositioncomprising one or more anti-androgen agents and one or moreantibiotic/anti-inflammatory agents or pharmaceutically acceptable saltsor hydrates thereof, useful for the treatment of a dermatologicaldisorder such as acne. The therapy combination of the present inventionprovides a synergistic effect in treating a subject with adermatological disorder.

The present invention also provides a method for treating or preventinga dermatological disorder by administering a pharmaceutical compositioncomprising one or more anti-androgen agents and one or moreantibiotic/anti-inflammatory agents or pharmaceutically acceptable saltsor hydrates thereof.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides novel pharmaceutical compositions comprising oneor more anti-androgen agents and one or moreantibiotic/anti-inflammatory agents as a combination of separate activeagents or as a combined composition comprising both active agents. Suchcompositions are useful for suppressing, inhibiting, preventing,alleviating or treating a dermatological disorder, including, but notlimited to, acne vulgaris, telogen effluvium, androgenetic alopecia, andacne rosacea.

The combination of the present invention can be administered at any timeand in any effective form. The anti-androgen agent and theantibiotic/anti-inflammatory agent may be administered simultaneously,e.g., as a single combination or dosage unit (e.g., a pill or liquidcontaining both compositions), or they may be administered as separatecompositions, but at the same time (e.g., where one drug is administeredintravenously and the other is administered orally or intramuscularly).The anti-androgen agent and the antibiotic/anti-inflammatory agent mayalso be administered sequentially at different times.

It is understood that the anti-androgen agents andantibiotic/anti-inflammatory agents of the present invention include allanalogs, isomers, metabolites, derivatives, pharmaceutically acceptablesalts, N-oxides, hydrates or any combination thereof.

Anti-Androgen Agents:

Examples of general anti-androgen agents used singly or in combinationin the present invention are, but not limited to, oral contraceptives,estrogen analogs, progesterone analogs, spironolactone, inocoteroneacetate, cyproterone acetate, flutamide, nilutamide, bicalutamide,ketoconazole, finasteride, dutasteride, bexlosteride, izonsteride,epresteride, turosteride, an isoflavanoid, RU-58642, RU-56279, WS9761 Aand B, RU-59063, RU-58841, bexlosteride, LG-2293, L-245976, LG-121071,LG-121091, LG-121104, LGD-2226, LGD-2941, YM-92088, YM-175735, LGD-1331,LGD-3303, BMS-357597, S-0503, BMS-482404, EM-4283, EM-4977, BMS-564929,BMS-391197, BMS-434588, BMS-487745, BMS-501949, SA-766, YM-92088,YM-580, LG-123303, LG-123129, PMCol, YM-175735, BMS-591305, BMS-591309,BMS-665139, BMS-665539, CE 590, 116BG33, 154BG31, arcarine, ACP-105,flutamide, hydroxyflutamide, bicalutamide, nilutarnide, hydroxysteroiddehydrogenase inhibitors, PPARα ligands such as bezafibrate,fenofibrate, gemfibrozil; PPARγ ligands such as darglitazone,pioglitazone, rosiglitazone, isaglitazone, rivoglitazone, netoglitazone;dual acting PPAR ligands, such as naveglitazar, farglitazar,tesaglitazar, ragaglitazar, oxeglitazar, PN-2034, PPAR δ;17-ketoreductase inhibitors, 3β-DHΔ4,6-isomerase inhibitors,3β-DHΔ4,5-isomerase inhibitors, 17,20 desmolase inhibitors, p450c17inhibitors, p450ssc inhibitors, and 17,20-lyase inhibitors, or mixturesthereof. The most preferred anti-androgen agents used in the presentinvention are spironolactone and an isoflavanoid.

Isoflavanoids (as illustrated below by the left-hand structure) orisoflavonoids (as illustrated below by the right-hand structure) thatmay be used in the present invention may have any of the followingchemical formulae:

wherein R¹-R⁹ may independently be H, OH, C₁₋₁₀ alkyl, C₁₋₁₀ alkenyl,alkynyl, vinyl, N₃, CN, Cl, Br, F, I, NO₂, C(O)O(C₁₋₁₀ alkyl),C(O)O((C₁₋₁₀ alkyl)), C(O)O(C₁₋₁₀ alkynyl), C(O)O(C₁₋₁₀ alkenyl),P(C₁₋₁₈ acyl), O((C₁₋₁₀ alkyl)), O(C₁₋₁₀ alkenyl), S(C₁₋₁₈ acyl),S((C₁₋₁₀ alkyl)), S(C₁₋₁₀ alkynyl), alkenyl), SO(C₁₋₁₈ acyl), SO((C₁₋₁₀alkyl)), SO(C₁₋₁₀ alkynyl), SO(C₁₋₁₀ alkenyl), SO₂(C₁₋₁₈ acyl),SO₂(C₁₋₁₀ alkyl), SO₂(C₁₋₁₀ alkynyl), SO₂(C₁₋₁₀ alkenyl), O₃S(C₁₋₁₈acyl), O₃S(C₁₋₁₀ alkyl), O₃S(C₁₋₁₀ alkenyl), NH₂, NH((C₁₋₁₀ alkyl)),NH(C₁₋₁₀ alkenyl), NH(C₁₋₁₀ alkynyl), NH(C₁₋₁₈ acyl), alkyl)₂, N(C₁₋₁₈acyl)₂, wherein alkyl, alkynyl, alkenyl and vinyl are optionallysubstituted by N3, CN, one to three halogen (Cl, Br, F, I), NO₂,C(O)O(C₁₋₁₀ alkyl), C(O)O(C₁₋₁₀ alkyl), C(O)O(C₁₋₁₀ alkynyl),C(O)O(C₁₋₁₀ alkenyl), O(C₁₋₁₈ acyl), alkyl), O(C₁₋₁₀ alkenyl), S(C₁₋₁₈acyl), S((C₁₋₁₀ alkyl)), S(C₁₋₁₀ alkynyl), alkenyl), SO(C₁₋₁₈ acyl),SO((C₁₋₁₀ alkyl)), SO(C₁₋₁₀ alkynyl), SO(C₁₋₁₀ alkenyl), SO₂(C₁₋₁₈acyl), SO₂(C₁₋₁₀ alkyl), SO₂(C₁₋₁₀ alkynyl), SO₂(C₁₋₁₀ alkenyl),O₃S(C₁₋₁₈ acyl), O₃S((C₁₋₁₀ alkyl)), O₃S(C₁₋₁₀ alkenyl), NH₂, NH((C₁₋₁₀alkyl)), NH(C₁₋₁₀ alkenyl), NH(C₁₋₁₀ alkynyl), NH(C₁₋₁₈ acyl), N((C₁₋₁₀alkyl))₂, and N(C₁₋₁₈ acyl)₂.

One such isoflavanoid is equol. Equol (4′,7-isoflavandiol) is anisoflavandiol metabolized from daidzein, a type of isoflavone, bybacterial flora in the intestines. It is also produced commercially.While endogenous estrogenic hormones such as estradiol are steroids,equol is a nonsteroidal estrogen. In the current invention, the “S-”form is preferred. S-Equol preferentially activates estrogen receptortype β. S-Equol has the structure:

It is appreciated that compounds of the present invention may havechiral centers and may exist in and be isolated in optically active andracemic forms. Some compounds may exhibit polymorphism. It is to beunderstood that the present invention encompasses any racemic, opticallyactive, diastereomeric, polymorphic, tautomeric, or stereoisomeric form,or mixtures thereof, of a compound of the invention, which possess theuseful properties described herein. It being well known in the art howto prepare optically active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically active starting materials, by chiral synthesis, or bychromatographic separation using a chiral stationary phase).

Antibiotic/Anti-Inflammatory Agents:

Examples of general antibiotic or anti-inflammatory agents used singlyor in combination in the present invention are, but are not limited to,mupirocin, neomycin sulfate bacitracin, polymyxin B, 1-ofloxacin,clindamycin phosphate, gentamicin sulfate, metronidazole,hexylresorcinol, methylbenzethonium chloride, phenol, quaternaryammonium compounds, tea tree oil, steroidal agents such ascorticosteroids such as hydrocortisone, hydroxyltriamcinolonealphamethyl dexamethasone, dexamethasonephosphate, beclomethasonedipropionate, clobetasol valerate, desonide, desoxymethasone,desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasonediacetate, diflucortolone valerate, fluadrenolone, fluclaroloneacetonide, fludrocortisone, flumethasone pivalate, fluosinoloneacetonide, fluocinonide, flucortine butylester, fluocortolone,fluprednidene, (fluprednylidene) acetate, flurandrenolone, halcinonide,hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone,triamcinolone acetonide, cortisone, cortodoxone, flucetonide,fludrocortisone, difluorosone diacetate, fluradrenalone acetonide,medrysone, amciafel, amcinafide, betamethasone, chlorprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylproprionate, hydrocortamate, meprednisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, betamethasonedipropionate, triamcinolone, non-steroidal agents such as COXinhibitors, LOX inhibitors, p38 kinase inhibitors, immunosuppressantagents such as, cyclosporin and cytokine synthesis inhibitors,tetracycline, minocycline, and doxycycline, or any combination thereof.The most preferred antibiotic agents are tetracycline, minocycline, anddoxycycline.

Dermatological Disorder:

Examples of general dermatological disorders that are suppressed,inhibited, prevented, alleviated or treated in the present inventionare, but are not limited to, dermatological pain, dermatologicalinflammation, acne, acne vulgaris, inflammatory acne, non-inflammatoryacne, acne fulminans, nodular papulopustular acne, acne conglobata, acnerosacea, rosacea, acne excoriee, acne associated with endocrinedisorders such as polycystic ovarian syndrome (PCOS) or Stein-Leventhalsyndrome, dermatitis, bacterial skin infections, fungal skin infections,viral skin infections, parasitic skin infections, skin neoplasia, skinneoplasms, pruritus, cellulitis, acute lymphangitis, lymphadenitis,erysipelas, cutaneous abscesses, necrotizing subcutaneous infections,scalded skin syndrome, folliculitis, furuncles, hidradenitissuppurativa, carbuncles, paronychial infections, rashes, erythrasma,impetigo, ecthyma, yeast skin infections, warts, molluscum contagiosum,trauma or injury to the skin, post-operative or post-surgical skinconditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis,pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous,erythema multiform, erythema nodosum, granuloma annulare, epidermalnecrolysis, sunburn, photosensitivity, pemphigus, bullous pemphigoid,dermatitis herpetiformis, keratosis pilaris, callouses, corns,ichthyosis, skin ulcers, ischemic necrosis, miliaria, hyperhidrosis,moles, Kaposi's sarcoma, melanoma, malignant melanoma, basal cellcarcinoma, squamous cell carcinoma, poison ivy, poison oak, contactdermatitis, atopic dermatitis, purpura, moniliasis, candidiasis,baldness, androgenetic alopecia, Behcet's syndrome, cholesteatoma,Dercum disease, ectodermal dysplasia, gustatory sweating, nail patellasyndrome, lupus, hives, telogen effluvium, Hailey-Hailey disease,chemical or thermal skin burns, scleroderma, aging skin, wrinkles, sunspots, necrotizing fasciitis, necrotizing myositis, gangrene, scarring,and vitiligo. The preferred dermatological disorders treated with thecomposition of the present invention are acne vulgaris, telogeneffluvium, androgenetic alopecia, and acne rosacea.

Administration:

The pharmaceutical composition of the present invention may beadministered in any form by any effective route, including, e.g., oral,parenteral, enteral, intravenous, suppository, intraperitoneal, topical,transdermal (e.g., using any standard patch), ophthalmic, nasally,local, non-oral, such as aerosal, inhalation, subcutaneous,intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, andintrathecal, etc. They can be administered alone, or in combination withany ingredient(s), active or inactive. The preferred route ofadministration is oral.

The pharmaceutical composition may be administered as a solid dosageform such as a tablet, capsule, pills, granules, pellets, powders, andthe like. The solid dosage form of the present invention may comprise acoating which is resistant to gastric juices and dissolves as a functionof the pH value of the release environment. By means of this coating, itis possible to ensure that the dosage form according to the presentinvention is delivered to its intended target. The crush resistantcoating which is resistant to gastric juices may dissolve at a pH valueof between 1 and 14.

The solid dosage form of the present invention may exhibit crushresistance to mechanical strength over a wide temperature range of, forexample, −25° C. to 40° C. The crush resistance may make the presentinvention virtually impossible to comminute or pulverise by chewing,grinding in a mortar, pounding, or any other means. As a consequence ofthe resistance to crushing, sustained release is maintained and anoverdose due to improper handling of the dosage form is effectivelyprevented.

The pharmaceutical composition may also be administered as a liquiddosage form such as solutions, suspensions, dispersions, emulsions,foams, gels, oils, and the like.

The pharmaceutical composition of this invention may be administered byintravenous, intraarterial, or intramuscular injection of a liquidpreparation. Suitable liquid formulations include solutions,suspensions, dispersions, emulsions, oils and the like.

The pharmaceutical composition may be administered topically to bodysurfaces, and is thus formulated in a form suitable for topicaladministration. Suitable topical formulations include liposomal beads,gels, ointments, creams, lotions, drops and the like. For topicaladministration, the anti-androgen agent and theantibiotic/anti-inflammatory agent are prepared and applied assolutions, suspensions, or emulsions in a physiologically acceptablediluent with or without a pharmaceutical carrier. For topicalapplication, admixture of the compounds with conventional creams,lotions, or delayed release patches is acceptable. Such a cream orlotion may comprise any agent described herein, and, may be used totreat a dermatological disorder.

The liposomal beads that may be used in the present invention maycontrol and increase concentration of the anti-androgen agent and theantibiotic/anti-inflammatory agent released at or near the desiredtarget site of administration, thus enabling the user to control thelocus and levels of the anti-androgen agent and theantibiotic/anti-inflammatory agent where it is most needed.

The benefit of having the anti-androgen agent and theantibiotic/anti-inflammatory agent in bead form is that they are not indirect contact with other active or inert suspensions including otherliposomes. This includes second and third levels of bead formation andlevels of hardening encapsulation.

The pharmaceutical composition may be administered as a suppository, forexample a rectal suppository or a urethral suppository. Further, thepharmaceutical composition is administered by subcutaneous implantationof a pellet. The pellet may provide controlled release of a compound asherein described over a period of time.

The pharmaceutical composition of the present invention is primarily foradministration to a host, which may comprise mammals, and particularlyhumans. It is expected that the physician will determine the actualdosage and duration of treatment, which will be most suitable for anindividual and can vary with the age, weight and response of theparticular individual.

Formulations

The final pharmaceutical composition of the present invention maycomprise from about 5 mg to about 2000 mg of an anti-androgen agent,from about 0.01 mg to about 5000 mg of an isoflavanoid, and from about 5mg to about 2000 mg of an antibiotic/anti-inflammatory agent.

The preferred pharmaceutical composition of the present invention maycomprise from about 25 mg to about 200 mg of an anti-androgen agent,from about 0.1 mg to about 500 mg of an isoflavanoid, and from about 50mg to about 200 mg of an antibiotic/anti-inflammatory agent.

The pharmaceutical composition may be formulated with, but not limitedto, pharmaceutically acceptable carriers or diluents, fillers, polymers,glidants, and lubricants.

Suitable pharmaceutically acceptable carriers include, but are notlimited to, water, salt solutions, alcohols, gum arabic, vegetable oils,benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such aslactose, amylose or starch, magnesium stearate, talc, silicic acid,viscous paraffin, white paraffin, glycerol, alginates, hyaluronic acid,collagen, perfume oil, fatty acid monoglycerides and diglycerides,pentaerythritol fatty acid esters, hydroxy methylcellulose, andpolyvinyl pyrrolidone. The carrier may also comprise any of thesubstances described in Remington: The Science and Practice of Pharmacy(Gennaro and Gennaro, Eds, 20th edition, Lippincott Williams & Wilkins,2000); Theory and Practice of Industrial Pharmacy ((Lachman et al.,eds., 3rd edition, Lippincott Williams & Wilkins, 1986); Encyclopedia ofPharmaceutical Technology (Swarbrick and Boylan, eds., 2nd edition,Marcel Dekker, 2002).

The fillers can be chosen from, but are not limited to, powderedcellulose, sorbitol, mannitol, various types of lactose, phosphates andthe like.

The polymers can be chosen from, but not limited to, hydrophilic orhydrophobic polymers such as derivatives of cellulose (for examplemethylcellulose, hydroxypropyl cellulose, hypromellose, ethylcellulose);polyvinylpirolidone (for example povidone, crospovidone, copovidone);polymethacrylates (for example Eudragit RS, RL); lypophillic components(for example glyceryl monostearate, glyceryl behenate); and variousother substances such as for example hydroxypropyl starch, polyethyleneoxide, carrageenan and the like. Most commonly, hydrophilic swellingpolymers of suitable viscosity such as hypromellose are used, preferablyin amounts above 5%, and more preferably above 8%.

Glidants can be chosen from, but not limited to, colloidal silicondioxide, talc, magnesium stearate, calcium stearate, aluminium stearate,palmitic acid, stearic acid, stearol, cetanol, polyethylene glycol andthe like.

Lubricants can be chosen from, but not limited to, stearic acid,magnesium stearate, calcium stearate, aluminium stearate, sodium stearylfumarate, talc, hydrogenated castor oil, polyethylene glycols and thelike.

The active ingredients of the present invention can be formulated intothe composition as neutralized pharmaceutically acceptable salt forms.Pharmaceutically acceptable salts include, but are not limited to, theacid addition salts, which are formed with inorganic acids such as, forexample, hydrochloric, sulfuric or phosphoric acids, or such organicacids as acetic, oxalic, tartaric, mandelic, citric and the like. Saltsformed from the free carboxyl groups can also be derived from inorganicbases such as, for example, sodium, potassium, ammonium, calcium, orferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

The pharmaceutical composition of the present invention may beformulated for sustained release. The release rate of the active agentsis primarily controlled by dissolution of the active agents ingastrointestinal fluid and subsequent diffusion out of the tablet orcapsule independent of pH, but can also be influenced by physicalprocesses of disintegration and erosion of the tablet or capsule.Pharmaceutical compositions according to the invention achieve atherapeutic blood/plasma concentration of anti-androgen agent andantibiotic/anti-inflammatory agent in an individual for at least about 8to about 14 hours from a single dose. The anti-androgen agent andantibiotic/anti-inflammatory agent may be released from the tablet orcapsule to result in a therapeutic blood/plasma concentration for atabout 8, 9, 10, 11, 12, 13 or 14 hours from a single dose.

The pharmaceutical composition may be an immediate release composition,i.e., a composition in which the whole quantity of the anti-androgenagent and/or the antibiotic/anti-inflammatory agent is releasedimmediately after administration. Such immediate release compositionsdisperse readily to form a suspension or solution of the active agentsafter mixing with the saliva, which is easily swallowed by the patients.These are particularly suitable for children or aged patients who havedifficulty in chewing and/or swallowing an intact tablet/capsule.

The anti-androgen agent and antibiotic/anti-inflammatory agent may beformulated as micronized or non-micronized particles. The non-micronizedparticles refer to particles having a particle size between 20-90microns. The micronized particles refer to particles having a particlesize between 1-20 microns. The particles may be formulated as solid orliquid dosage forms for oral administration.

The preparation of pharmaceutical compositions which contain an activecomponent is well understood in the art, for example by mixing,granulating, or tablet-forming processes. The active agent is oftenmixed with excipients which are pharmaceutically acceptable andcompatible with the active agent. For oral administration, theanti-androgen agent and/or the antibiotic/anti-inflammatory agent ofthis invention or their physiologically tolerated derivatives such assalts, esters, N-oxides, and the like are mixed with additives customaryfor this purpose, such as vehicles, stabilizers, or inert diluents, andconverted by customary methods into suitable forms for administration,such as tablets, coated tablets, hard or soft gelatin capsules, aqueous,alcoholic or oily solutions. For parenteral administration, thecompounds of this invention or their physiologically toleratedderivatives such as salts, esters, N-oxides, and the like are convertedinto a solution, suspension, or emulsion, if desired with the substancescustomary and suitable for this purpose, for example, solubilizers orother.

One of ordinary skill in the art will appreciate that the individualcomponents of the present invention may change depending on the physicaland chemical qualities needed for the pharmaceutical compositions in agiven process and/or application to which the pharmaceuticalcompositions will be applied.

ABBREVIATIONS AND DEFINITIONS

“Alkyl” is defined herein to mean, unless otherwise specified, asaturated straight, branched, or cyclic, primary, secondary, or tertiaryhydrocarbon of typically C₁ to C₁₀, and specifically includes methyl,trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl,t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl,cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and2,3-dimethylbutyl. The term includes both substituted and unsubstitutedalkyl groups. Alkyl groups can be optionally substituted with one ormore moieties selected from the group consisting of hydroxyl, amino,alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid,sulfate, phosphonic acid, phosphate, or phosphonate, or any other viablefunctional group that does not inhibit the pharmacological activity ofthis compound, either unprotected, or protected, as necessary, as knownto those skilled in the art, for example, as taught in T. W. Greene andP. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3rd ed., JohnWiley & Sons, 1999, hereby incorporated by reference.

“Acyl” is defined herein to mean, unless otherwise specified, acarboxylic acid ester in which the non-carbonyl moiety of the estergroup is selected from straight, branched, or cyclic alkyl, alkoxyalkylincluding methoxymethyl, aralkyl including benzyl, aryloxyalkyl such asphenoxymethyl, aryl including phenyl optionally substituted with halogen(F, Cl, Br, I), C₁ to C₄ alkyl or C₁ to C₄ alkoxy, sulfonate esters suchas alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di ortriphosphate ester, trityl or monomethoxytrityl, substituted benzyl,trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl. Arylgroups in the esters optimally comprise a phenyl group.

“Liposome” is defined herein to mean any enclosed vehicle made of alipid bilayer which can be used to deliver active agents.

“Active agent” is defined herein to mean a compound given to a host toelicit a desired effect.

“Synergistic” is defined herein to mean the joint action of the drugs issuch that the combined effect is greater than the algebraic sum of theirindividual parts.

“Pharmaceutical composition” is defined herein to mean a therapeuticallyeffective amount of the anti-androgen agent andantibiotic/anti-inflammatory agent.

“Therapeutically effective amount” is defined herein to mean an amountwhich provides a therapeutic effect for a given condition andadministration regimen.

“Pharmaceutically acceptable” is defined herein to mean any formulationwhich is safe, and provides the appropriate delivery for the desiredroute of administration of an effective amount of at least one compoundfor use in the present invention.

“Administering” is defined herein to mean bringing a subject in contactwith the combination of the present invention.

“Sustained release” is defined herein to mean that the anti-androgenagent and antibiotic/anti-inflammatory agent becomes available forbio-absorption in the gastrointestinal tract over a prolonged period oftime.

“Immediate release” is defined herein to mean a composition in which thewhole quantity of the anti-androgen agent andantibiotic/anti-inflammatory agent is released immediately afteradministration.

“Therapeutic blood/plasma concentration” is defined herein to mean aconcentration equal to at least about 50% of the AUC and/or C_(max) ofthe anti-androgen agent and antibiotic/anti-inflammatory agentadministered to a human subject.

The terms “suppressing”, “inhibiting”, “preventing”, “alleviating” or“treating” are defined herein to mean delaying the onset of symptoms,reducing the severity of symptoms, reducing the severity of an acuteepisode, reducing the number of symptoms, reducing the incidence ofdisease-related symptoms, reducing the latency of symptoms, amelioratingsymptoms, reducing secondary symptoms, reducing secondary infections,preventing relapse to a disease, decreasing the number or frequency ofrelapse episodes, increasing latency between symptomatic episodes,increasing time to sustained progression, expediting remission, inducingremission, augmenting remission, speeding recovery, or increasingefficacy of or decreasing resistance to alternative therapeutics.

EXAMPLES Example 1

Formulation

The preferred formulation for the disclosed composition (Formula 1) isdoxycycline hyclate (50 mg; antibiotic) and S-equol (5 mg;isoflavandiol). One skilled in the art will recognize that alternativeequivalent formulations are encompassed by this example.

Example 2

Formula 1 reduces comedones and inflammatory lesions and improves acnein patients.

Thirty-five patients (13-55 years of age) were enrolled in aplacebo-controlled study. Twenty-seven patients were treated with oraladministration of a capsule containing the ingredients of Formula 1 andeight patients were treated with a placebo capsule containing onlydoxycycline hyclate (50 mg). Patients received Formula 1 or placebotwice daily for twelve weeks. The number of comedones (“blackheads”) andnodular and inflammatory lesions (>2 mm in diameter) were counted on theface of each patient at baseline and at two weeks, six weeks and twelveweeks post-treatment. No serious untoward effects were observed ineither the treated or placebo groups.

Formula 1 significantly reduced the number of comedones and nodular andinflammatory lesions during the twelve week treatment cycle (Table 1).The results are shown as the change at baseline and the percent changefrom baseline for each outcome measure after twelve weeks of treatment.Data are reported as mean values (±standard error of the mean, SEM) foreach outcome measure. The results for ‘total lesions’ includes bothcomedones and inflammatory and nodular lesions.

TABLE 1 Summary Lesion Counts at 12-weeks¹ Treated Group Placebo Group(n = 27) (n = 8) Parameter Avg (SEM) Avg (SEM) Total Inflammatory andNodular Lesions Baseline 20.8(1.9) 14.3(2.8) 12-weeks  7.2(2.2) 7.0(3.4) Change from baseline −20.2(3.6)  −7.0(6.8) Change frombaseline, % −65.5% −50.9% Total Comedones Baseline 33.3(2.9) 26.9(8.1)12-weeks 19.3(4.3) 19.5(7.2) Change from baseline −18.3(6.3)  −7.3(9.1)Change from baseline, % −42.0% −27.4% Total Lesions Baseline 54.1(4.4)41.1(9.3) 12-weeks 26.5(6.2) 26.5(4.1) Change from baseline −36.8(10.3)−14.3(15.2) Change from baseline, % −51.0% −35.6% ¹Unless otherwiseindicated, data are mean (SE) number of lesions

The average number of comedones continued to decline with treatmentcompared to inconsistent observations of the placebo group. For example,Formula 1 treatment significantly reduced the number of comedones in thetreated group from 33.3 (±2.9) at baseline to 19.3 (±4.3; p=0.03) at 12weeks while a more varied response was observed for the placebo group(26.9, 29.0, 11.8 and 19.5 at baseline, week 2, week 6 and week 12,respectively). Thus, Formula 1 reduced the average number of comedonesby 42% at twelve weeks compared to baseline in the treatment group to27.4% reduction in the placebo group. Formula 1 was also 15% moreeffective in reducing the total number of lesions (including comedonesand inflammatory and nodular lesions) in the treatment group (51.0%)compared to the placebo group (35.6%) after twelve weeks of treatment.

Next, an Investigator Global Assessment (IGA) score measuring theimprovement of the appearance of inflammatory and nodular lesions andcomedones was determined for each patient at baseline and 2 weeks and 6weeks post-treatment. For this assessment the investigators were askedto evaluate whether their patient's lesions and comedones improved usinga score of 1 to 10 with 10 indicating the most improvement. Treatmentwith Formula 1 improved the IGA scores in the treated patients from 2.5at baseline to 4.0 at six weeks while the IGA scores in the placebogroup did not change (2.3 at baseline to 2.5 at six weeks).

Lastly, the Visia™ complexion analysis system was used to assess theaverage number of porphyrins, a measure of bacteria in pores, in eachpatient. Treatment with Formula 1 reduced the average number ofporphyrins in the treatment group while a slight increase in porphyrinswas observed in the placebo group (Table 2).

TABLE 2 Por (BL) Por(W2) Por (W6) Por (W12) Average (Drag) 50.6 46.420.4 15.5 Average (Placebo) 31.6 25.8 15.7 35.5 SEM (Drag) 13.6 11.9 5.53.7 SEM (Placebo) 15.7 8.7 5.5 18.0

In summary, this example shows that Formula 1 significantly reduced thenumber of comedones, inflammatory and nodular lesions by 15% compared tobaseline in the treatment group as well markedly reducing the number ofporphyrins during the course of the study.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

Although certain embodiments and examples have been described in detailabove, those having ordinary skill in the art will clearly understandthat many modifications are possible in the embodiments and exampleswithout departing from the teachings thereof. All such modifications areintended to be encompassed within the below claims of the invention.

What is claimed:
 1. A method of alleviating acne in a patient in needthereof, the method comprising simultaneously or sequentially orallyadministering, to the patient, a therapeutically effective amount of 5to 10 mg of 4′,7-isoflavandiol or a pharmaceutically acceptable salt orhydrate thereof, wherein the 4′,7-isoflavandiol or the pharmaceuticallyacceptable salt or hydrate thereof is the “S-” form, and 50 to 100 mg ofminocycline or a pharmaceutically acceptable salt or hydrate thereof. 2.The method of claim 1, wherein the 4′,7-isoflavandiol or thepharmaceutically acceptable salt or hydrate thereof and the minocyclineor the pharmaceutically acceptable salt or hydrate thereof areadministered simultaneously as a single dosage unit.
 3. The method ofclaim 1, wherein the 4′,7-isoflavandiol or the pharmaceuticallyacceptable salt or hydrate thereof and the minocycline or thepharmaceutically acceptable salt or hydrate thereof are administered asseparate compositions simultaneously or sequentially.
 4. The method ofclaim 1, wherein the method further comprises administering an oralcontraceptive, an estrogen analog, a progesterone analog,spironolactone, inocoterone acetate, cyproterone acetate, flutamide,nilutamide, bicalutamide, keto-conazole, finasteride, dutasteride,bexlosteride, izonsteride, epresteride, turosteride, isoflavanoid,RU-58642, RU-56279, WS9761 A and B, RU-59063, RU-58841, bexlosteride,LG-2293, L-245976, LG-121071, LG-121091, LG-121104, LGD-2226, LGD-2941,YM-92088, YM-175735, LGD-1331, LGD-3303, BMS-357597, S-40503,BMS-482404, EM-4283, EM-4977, BMS-564929, BMS-391197, BMS-434588,BMS-487745, BMS-501949, SA-766, YM-92088, YM-580, LG-123303, LG-123129,PMCol, YM-175735, BMS-591305, BMS-591309, BMS-665139, BMS-665539, CE590, 116BG33, 154BG31, arcarine, ACP-105, flutamide, hydroxyflutamide,bicalutamide, nilutarnide, a hydroxy-steroid dehydrogenase inhibitor, aPPARa ligand, a dual acting PPAR ligand, PN-2034, PPAR d, a17-ketoreductase inhibitor, a 3β-DHD4,6-isomerase inhibitor, a3β-DHD4,5-isomerase inhibitor, a 17,20 desmolase inhibitor, a p450c17inhibitor, a p450ssc inhibitor, or a 17,20-lyase inhibitor.
 5. Themethod of claim 1, wherein the acne is acne vulgaris or acne rosacea. 6.The method of claim 1, wherein the 4′,7-isoflavandiol and/or theminocycline is formulated for sustained release or delayed release. 7.The method of claim 1, wherein the 4′,7-isoflavandiol and/or theminocycline is formulated for immediate release.
 8. A method ofalleviating acne in a patient in need thereof, the method comprisingsimultaneously or sequentially orally administering, to the patient, atherapeutically effective amount of 4′,7-isoflavandiol or apharmaceutically acceptable salt or hydrate thereof, wherein the4′,7-isoflavandiol or the pharmaceutically acceptable salt or hydratethereof is the “S-” form, and minocycline or a pharmaceuticallyacceptable salt or hydrate thereof, wherein the minocycline and/or4′,7-isoflavandiol or a pharmaceutically acceptable salt or hydratethereof is formulated in a sustained release formulation.